A continuously challenging goal in the development of therapeutically useful drugs is to synthesize biologically active compounds that penetrate cells. Although a large number of drug candidates have been synthesized for the treatment of various diseases during the past few decades, many of these candidates have failed in clinical application because of low bioavailability. Therefore, significant efforts have been undertaken to improve the bioavailability of drugs and to increase their concentration in the bloodstream. The bioavailability of drugs depends significantly on the efficiency of transport into cells, which involves three concurrent steps including administration, membrane penetration, and distribution. To gain high bioavailability, drugs should be sufficiently polar for administration and distribution while sufficiently nonpolar for passive diffusion through the lipid bilayer of cell membranes. As a result, most drugs are limited to a narrow range of physical properties which be effective for the drug delivery process. Many highly promising and important drug candidates often fail to advance clinically because they fall out of this range and cannot achieve the desirable balance of water solubility and passive membrane translocation.
Recently, several efforts have been disclosed with respect to improving the cellular uptake of drug candidates into cells. See (1) WO 79/00515; (2) WO 94/04686; (3) WO 91/09958; (4) WO 98/52614; (5) Pepinsky, R. B. et al. DNA Cell Biol., 13, p. 1011-1019 (1994); (6) Vocero-Akbani, A. M. et al. Nat. Med., 5, p. 29-33 (1999); (7) Schwarze, S. R. et al. Science, 285, p. 1569-1572 (1999); (8) Ryser, H. J.-P. Nature (London), 215, 934-936 (1967); (9) Emi, N. et al. Biophys. Res. Commun., 231, p 421-424 (1997); (10) Ryser, H. J.-P. et al. Proc. Natl. Acad. Sci. USA., 75, p. 1872-1876 and 3867-3870 (1978); (11) Leonetti, J.-P. et al. Bioconjugate Chem., 1, p. 149-153 (1990); (12) Murphy, J. E. et al. Proc. Natl. Acad. Sci. U.S.A., 95, p. 1517-1522 (1998); (13) Buschle, M. et al. Proc. Natl. Acad. Sci. USA., 94, p. 3256-3261 (1997); (14) Mitchell. D. J. et al. J. Peptide Res., 55, p. 318-325 (2000); and (15) Wender. P. A. et al. Proc. Natl. Acad. Sci. U.S.A., 97, p. 13003 (2000). It has been disclosed that certain naturally occurring macromolecules including the HIV-1 protein Tat enter cells through an active transport mechanism. See references (5)-(7). It has also been reported that arginine-rich fragments of HIV-1 Tat are efficiently internalized by cultured cells. See references (2) and (3). Conjugation of oligo-arginine to small molecules or macromolecules has been disclosed as facilitating the delivery of the attached molecules into cells. See references (14) and (15). References (14) and (15) disclose that peptides containing 6 to 15 contiguous arginine residues can increase cellular uptake of conjugated molecules. These references also disclose that the peptoid analogs of 6 to 9 arginine residue peptides display even higher cellular uptake properties. Additionally, these references report that the chirality of the oligomers is not significant with respect to intracellular translocation and that the distance between the backbone and the guanidine head group of these materials is important in transport activity.
Despite the apparent success in the use of peptide-based molecule transporters, including peptides and peptoids derived from arginine, lysine (see reference (8)), and ornithine (see reference (9)), such molecules are limited by their toxicity, availability, and cost. Furthermore, peptide-based molecule transporters may not be sufficiently stable toward intracellular and extracellular protease activity. Upon degradation, such molecules lose their efficacy as molecular transporters. In addition, peptide-based molecules also suffer from the drawback that such molecules may trigger antigenic responses and may thus be unsuitable for long term use in a patient. Therefore, a need remains for compounds and methods for transporting biologically active molecules such as drugs into cells which exhibit improved efficacy, stability, and which are not cost-prohibitive.